Design and Synthesis of New Quinoxaline‐Oxazole‐Morpholino Conjugates; Evaluation of Anticancer Activity and In Silico Molecular Docking and ADMET Studies

Abstract In this paper, we report the synthesis of targeted quinoxaline‐oxazole‐morpholino conjugates ( 5a–n ) in a conventional three‐step procedure from 3‐chloroquinoxalin‐2(1 H )‐one. The anticancer activity was assessed against two human cancer cell lines, including MCF‐7 (breast) and HepG2 (liver), using the MTT assay method. In this study, Erlotinib was used as the standard drug. The anticancer activity results show that the compounds 5g (MCF‐7 = 1.20 ± 0.10 and HepG2 = 1.04 ± 0.05 µM), 5f (MCF‐7 = 1.29 ± 0.10 and HepG2 = 1.10 ± 0.06 µM), and 5e (MCF‐7 = 1.72 ± 0.10 and HepG2 = 1.45 ± 0.12 µM) exhibited more potent anticancer activity as compared to the standard drug Erlotinib. In a cell survivability test (MCF‐10A), all the three potent compounds ( 5g , 5f , and 5e ) were evaluated against the normal breast cell line, although neither of them displayed any significant cytotoxicity with IC 50 values greater than 88 .02 µM. In addition to this, molecular docking studies of compounds 5g , 5f , and 5e demonstrated that these compounds had more EGFR‐binding interactions. The potent compounds were further screened for their in vitro tyrosine kinase EGFR inhibitory activity using Erlotinib as the reference drug. The two compounds, 5g and 5f , display the highest tyrosine kinase EGFR inhibitory potency than the reference Erlotinib. The active compounds 5g , 5f , and 5e were subjected to in silico pharmacokinetic assessment by SWISS, ADME, and pkCSM. The three compounds, 5g , 5f , and 5e , followed Lipinski, Veber, Egan, and Muegge rules without any deviation.